SINGLE CHANNEL ANALYSIS OF THE EFFECTS OF HALOTHANE ON THE NICOTINIC ACETYLCHOLINE RECEPTOR CHANNEL (CHOLESTEROL, CELL CULTURE, PATCH CLAMP, GENERAL ANESTHETIC).

Persistent Link:
http://hdl.handle.net/10150/187831
Title:
SINGLE CHANNEL ANALYSIS OF THE EFFECTS OF HALOTHANE ON THE NICOTINIC ACETYLCHOLINE RECEPTOR CHANNEL (CHOLESTEROL, CELL CULTURE, PATCH CLAMP, GENERAL ANESTHETIC).
Author:
LECHLEITER, JAMES DONALD.
Issue Date:
1984
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Anesthesia, a state of being absent of sensation and consciousness, has been recognized since antiquity. Even today anesthesia is still best characterized by the lack of consciousness and sensations. Since anesthetic potency is correlated with lipid solubility, the site of action of general anesthetics has been thought to be hydrophobic in nature and to involve excitable membranes critical for interneuronal communications. Thus, general anesthetics may interact directly with functionally-relevant membrane proteins (via hydrophobic pockets) or indirectly, with the lipids surrounding these proteins. To better understand the details of general anesthetic action, I examined how halothane interacts with a functional synaptic protein, the acetylcholine receptor channel embedded in the membranes of cultured Xenopus myocytes. Next, I examined how changing the lipid composition, of these membranes, affected this interaction. Using the extracellular patch-clamp technique, I found that halothane, at clinically-relevant concentrations, shortened the burst duration of single receptor channels without affecting their conductance. Moreover, the halothane-induced reduction of burst durations was significantly attenuated after pretreatment with cholesterol-rich lipsomes which increased significantly the cholesterol content of these cells. These findings provide the first direct support for the role of membrane lipids in the mechanism of GA action. In particular, I demonstrated that increases in membrane cholesterol antagonize the anesthetic action of halothane. Although direct action of cholesterol on synaptic proteins cannot be ruled out, my data strongly suggest that membrane lipids are involved at a critical, but as yet undefined, site with which GAs interact. The exact manner by which increases in membrane cholesterol antagonize GA action remains to be eludicated.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Anesthetics -- Physiological effect.; Halothane -- Physiological effect.; Lipid membranes -- Effect of drugs on.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Physiology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Gruener, Raphael

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleSINGLE CHANNEL ANALYSIS OF THE EFFECTS OF HALOTHANE ON THE NICOTINIC ACETYLCHOLINE RECEPTOR CHANNEL (CHOLESTEROL, CELL CULTURE, PATCH CLAMP, GENERAL ANESTHETIC).en_US
dc.creatorLECHLEITER, JAMES DONALD.en_US
dc.contributor.authorLECHLEITER, JAMES DONALD.en_US
dc.date.issued1984en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractAnesthesia, a state of being absent of sensation and consciousness, has been recognized since antiquity. Even today anesthesia is still best characterized by the lack of consciousness and sensations. Since anesthetic potency is correlated with lipid solubility, the site of action of general anesthetics has been thought to be hydrophobic in nature and to involve excitable membranes critical for interneuronal communications. Thus, general anesthetics may interact directly with functionally-relevant membrane proteins (via hydrophobic pockets) or indirectly, with the lipids surrounding these proteins. To better understand the details of general anesthetic action, I examined how halothane interacts with a functional synaptic protein, the acetylcholine receptor channel embedded in the membranes of cultured Xenopus myocytes. Next, I examined how changing the lipid composition, of these membranes, affected this interaction. Using the extracellular patch-clamp technique, I found that halothane, at clinically-relevant concentrations, shortened the burst duration of single receptor channels without affecting their conductance. Moreover, the halothane-induced reduction of burst durations was significantly attenuated after pretreatment with cholesterol-rich lipsomes which increased significantly the cholesterol content of these cells. These findings provide the first direct support for the role of membrane lipids in the mechanism of GA action. In particular, I demonstrated that increases in membrane cholesterol antagonize the anesthetic action of halothane. Although direct action of cholesterol on synaptic proteins cannot be ruled out, my data strongly suggest that membrane lipids are involved at a critical, but as yet undefined, site with which GAs interact. The exact manner by which increases in membrane cholesterol antagonize GA action remains to be eludicated.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectAnesthetics -- Physiological effect.en_US
dc.subjectHalothane -- Physiological effect.en_US
dc.subjectLipid membranes -- Effect of drugs on.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGruener, Raphaelen_US
dc.identifier.proquest8504123en_US
dc.identifier.oclc693399033en_US
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